Process for manufacture of quaternary ammonium tosylate salts of cinnamidoalkylamines and / or benzamidoalkylamines

ABSTRACT

An efficient, simple, high yielding, eco-friendly process for the manufacture of tosylates quaternary ammonium salts of cinnamidoalkylamines and/or benzamidoalkylamines (Formula I) has been described. These compounds are substantive UV-absorbers. They are useful in making fabric care products and personal care products. 
     
       
         
         
             
             
         
       
     
     The scope of this methodology has been demonstrated by converting water soluble organic sunscreen quaternary halides to their corresponding tosylates of Formula VI.

This application is a division of U.S. application Ser. No. 10/682,004filed on Oct. 8, 2003 now U.S. Pat. No. 7,045,139. Such application isincorporated herein by reference.

FIELD OF INVENTION

This invention relates to a novel process for manufacture of cationic,quaternary ammonium tosylate salts of cinnamidoalkylamines and/orbenzamidoalkylamines of Formula I. This invention particularly relatesto the synthesis of non-hydrolyzable, non-irritating UV-absorbers havingsubstantivity to cotton, wool, skin and hair.

-   ArCO is selected from p-N,N-dimethylamino benzoyl and/or p-methoxy    cinnamoyl;-   R₁ is selected from H or alkyl groups containing from 1 to 6 carbon    atoms;-   R₂ and R₃ are independently selected from alkyl groups containing    from 1 to 12 carbon atoms;-   R₄ is selected from alkyl or alkenyl groups containing from 8 to 22    carbons; and-   n is an integer having values from 1 to 6.

BACKGROUND AND PRIOR ART

Quaternised UV-absorbers with tosylate anion are of significance fortheir substantivity to skin and hair as well as their mildness comparedto the corresponding quaternary halides [Soap, Perfumery & Cosmetics,29–34, March 1997].

U.S. Pat. No. 4,680,144 (1987) and U.S. Pat. No. 5,427,773 (1995)disclose preparations of these kind of cationic substantive photofilterslike dodecyl dimethyl amino benzamido propyl dimethyl ammonium tosylate.In this process, a primary amino group of N,N-dimethyl propyl diamine isreacted with dimethyl amino benzoic acid to form an amidoamine and thenthe tertiary amino group of the amidoamine is quaternised with alkyltosylate. Similarly, U.S. Pat. No. 6,613,340 (2003) discloses cationictosylate salts from cinnamidoalkylamines following the same methodology.The procedures described in these patents are very tedious where alkyltosylates that are used for quaternisation are in turn prepared fromfatty alcohols and tosyl chloride. This tosylation reaction is done in asuitable solvent using stoichiometric quantities of tertiary amine baseslike triethylamine or pyridine. The organic bases mop up thehydrochloric acid generated and the subsequent hydrochloride-base saltthat is formed as a by-product has to be removed by washing the reactionmixture with water. This significantly increases the effluent load.Another disadvantage of this process from prior art is that the reactionfor preparation of alkyl tosylates is carried out in either halogenatedsolvents like dichloromethane or aromatic solvents. Purification ofalkyl tosylate also results in significant loss of yield andsimultaneous increase in effluent treatment. This purification step isnecessary due to the presence of unconverted fatty alcohols in alkyltosylates. The quaternisation of cinnamidoalkylamines and/orbenzamidoalkylamines with alkyl tosylate does not give quantitativeconversion and hence after the purification step isolated yields ofquaternised UV-absorbers range between 65 to 70% only.

In summary, all these factors make the process for making quaternisedUV-absorbing tosylates not only tedious and expensive but alsonon-environment friendly. Hence, there is a need for a simple,quantitative and eco-friendly process for making these substantiveUV-absorbers that are superior to the corresponding halides due totosylate as counter ion.

SUMMARY OF THE INVENTION

The present invention provides a novel, efficient, high yielding andenvironmental friendly process for preparing quaternary ammoniumtosylate salts of cinnamidoalkylamines and/or benzamidoalkylamines ofFormula I, wherein;

-   ArCO is selected from p-N,N-dimethylamino benzoyl and/or p-methoxy    cinnamoyl;-   R₁ is selected from H or alkyl groups containing from 1 to 6 carbon    atoms;-   R₂ and R₃ are independently selected from alkyl groups containing    from 1 to 12 carbon atoms;-   R₄ is selected from alkyl or alkenyl groups containing from 8 to 22    carbons; and-   n is an integer having values from 1 to 6, the process comprising    the steps of    -   i) quaternisation of 1.0 mole of cinnamidoalkylamine and/or        benzamidoalkylamine of Formula II with 1.0 mole of alkylating        compound of Formula III, wherein, R₁, R₂, R₃, R₄ and n is same        as that in the compound of said Formula I, with or without        solvent, to obtain a quaternary ammonium halide of Formula IV;

-   -   (ii) treating the aqueous solution of quaternary ammonium halide        of Formula IV obtained in step (i) with stoichiometric quantity        of sodium p-toluene sulphonate to get water insoluble quaternary        ammonium tosylate of Formula I.

The methodology described in the present invention is generally usefulfor converting water-soluble quaternary organic sunscreen ammoniumhalides (Formula V) to water insoluble quaternary sunscreen ammoniumtosylates (Formula VI).

DETAILED DESCRIPTION OF THE INVENTION

The process of making compounds of Formula I described in the presentinvention comprises of two steps, a) synthesis of quaternary ammoniumhalides of Formula IV and b) conversion of water-soluble quaternaryammonium halides of Formula IV to water-insoluble quaternary ammoniumtosylates of Formula I.

A) Synthesis of Quaternary Ammonium Halides of Formula IV.

The UV-absorbing ciniamidoalkylamines and/or benzamidoalkylamines ofFormula II are synthesised as per the literature procedures [U.S. Pat.No. 5,427,773 (1995), U.S. Pat. No. 6,613,340 (2003)]. These amidoaminesare quaternised using commercially available alkyl halides of FormulaIII in aqueous/alcoholic medium to give quantitative generation ofcorresponding water-soluble, UV-absorbing, quaternary ammonium halidesof Formula IV.

The quaternisation reaction can be conveniently done in a pressurereactor as well as in an open system. The temperatures suitable forpressure reaction range from about 100–135° C. with the pressures up to50 psi. The choice of solvent generally dictates reaction conditionsincluding selection of closed reactor or open vessel. Water as a solventand a pressure reactor are the most preferred conditions since thesubsequent step is done in aqueous medium. Any other polar solvent maybe used for quaternisation, however, in that case solvent has to beremoved and replaced by water for second step. The progress of thequaternisation reaction is monitored by measuring the amount ofunreacted alkylating agent by chromatography or by estimation ofunquaternized amidoamine or by estimation of X⁻, the halide anion.

Alternately, quaternisations can be carried out by directly reactingcinnamidoalkylamines and/or benzamidoalkylamines of Formula II withalkyl halides of Formula III at from about 100 to 140° C. for 4 to 24hours without any solvent and in an inert atmosphere of nitrogen. Theprogress of the reaction is monitored by estimation of unquaternisedtertiary amine as well as by the estimation of liberated halide.

b) Conversion of Water Soluble Quaternary Compounds of Formula IV toWater-insoluble Quaternary Ammonium Tosylates.

The aqueous solution (30%) of quaternary sunscreen ammonium halides ofFormula IV of step (i) is then treated with equimolar quantities ofsodium p-toluene sulphonate at room temperature. This results inquantitative precipitation of corresponding tosylates of Formula I. Theprecipitates are then washed off with copious amount of water and driedunder vacuum to give quaternary sunscreen ammonium tosylates of FormulaI.

In another embodiment, the process of the present invention relates tomanufacture of quaternary ammonium tosylates of Formula I, in which ArCOis selected from p-N,N-dimethylamino benzoyl and/or p-methoxy cinnamoyl;R₁ is selected from H or alkyl groups containing from 1 to 6 carbonatoms, R₂ and R₃ are independently selected from alkyl groups containingfrom 1 to 12 carbon atoms; R₄ is selected from alkyl or alkenyl groupscontaining from 8 to 22 carbons; n is an integer having values from 1 to6; from the compounds of Formula II, III, IV and sodium p-toluenesulphonate, with respective substituents ArCO, R₁, R₂, R₃, and n ofFormula II, R₄ of Formula III and ArCO, R₁, R₂, R₃, R₄, and n of FormulaIV as defined for the compounds of Formula I in this embodiment.

In another embodiment, the process of the present invention relates tomanufacture of a quaternary ammonium tosylate of Formula I, in whichArCO=p-methoxy cinnamoyl, R₁=H, R₂, R₃=—CH₃, R₄=—C₁₂H₂₅ and n=3, fromthe compound of Formula II (p-methoxy cinnamidopropyl dimethylamine,ArCO=p-methoxy cinnamoyl, R₁=H, R₂, R₃=—CH₃, n=3) quaternised withcompound of Formula III (lauryl chloride, R₄=—C₁₂H₂₅, X⁻=chloride anion)forming the quaternised compound of Formula IV (p-methoxycinnamidopropyl dimethyl lauryl ammonium chloride, R₁=H, R₂, R₃=—CH₃,R₄=—C₁₂H₂₅, n=3, X⁻=chloride anion), aqueous solution of which is thentreated with stoichiometric quantity of sodium p-toluene sulphonate.

In another embodiment, the process of the present invention relates tomanufacture of a quaternary ammonium tosylate of Formula I, in whichArCO=p-N,N-dimethylamino benzoyl, R₁=H, R₂, R₃=—CH₃, R₄=—C₁₂H₂₅ and n=3,from the compound of Formula II (p-N,N-dimethylaminobenzamidopropyldimethylamine, ArCO=p-N,N-dimethyl aminobenzoyl, R₁=H,R₂, R₃=—CH₃, n=3) quaternised with compound of Formula III (laurylchloride, R₄=—C₁₂H₂₅, X⁻=chloride anion) forming the quaternisedcompound of Formula IV (p-N,N-dimethylamino benzamidopropyldimethyllauryl ammonium chloride, R₁=H, R₂, R₃=—CH₃,R₄=—C₁₂H₂₅,n=3, X⁻=chloride anion), aqueous solution of which is thentreated with stoichiometric quantity of sodium p-toluene sulphonate.

This methodology is extended to a general procedure for convertingwater-soluble quaternary sunscreen ammonium halides to water insolublequaternary sunscreen ammonium tosylates. This is demonstrated by usingwater soluble bis quaternary UV-absorber of U.S. Pat. No. 6,426,435(2002).

In another embodiment, isopropanolic solution of quaternary sunscreenammonium bis-chloride of Formula V is treated with two equivalence ofsodium tosylate 80° C. for 8 hours. The separated sodium chloride isfiltered to give alcoholic solution of bis-quaternary sunscreen ammoniumtosylates of Formula VI.

In yet another embodiment, the process of the present invention relatesto manufacture of a quaternary ammonium tosylate of Formula VI, in whichArCO is selected from p-N,N-dimethylamino benzoyl and/or p-methoxycinnamoyl; R₁ is selected from H or alkyl groups containing from 1 to 6carbon atoms, R₂ and R₃ are independently selected from alkyl groupscontaining from 1 to 12 carbon atoms; n is an integer having values from1 to 6; m is an integer having values from 1 to 10; from the compoundsof Formula V and sodium p-toluene sulphonate, with respectivesubstituents ArCO, R₁, R₂, R₃, n and m of Formula V, as defined for thecompounds of Formula VI.

In yet another embodiment, the present invention relates to a waterinsoluble quaternary ammonium bis tosylates of Formula VI;

where; ArCO is selected from p-N,N-dimethylamino benzoyl and/orp-methoxy cinnamoyl;

-   R₁ is selected from H or alkyl groups containing from 1 to 6 carbon    atoms;-   R₂ and R₃ are independently selected from alkyl groups containing    from 1 to 12 carbon atoms;-   n is an integer having values from 1 to 6; and-   m is an integer having values from 1 to 10.

The processes described for quaternised UV-absorbing tosylate salts inU.S. Pat. No. 4,680,144 (1987), U.S. Pat. No. 5,427,773 (1995) and U.S.Pat. No. 6,613,340 (2003) are multi-step, low yielding and noneco-friendly. They involve use of p-toluene sulphonyl chloride as wellas halogenated solvents. Since the synthetic routes for alkyl tosylatesdescribed in these patents go via sulphonyl chloride, it necessitatesuse of an organic base. Thus, use of solvents, generation of by-productslike salt of organic base-hydrochloride and the necessary purificationsteps that result in not only lower yield of isolated product but heavyload on effluent treatment. This can be easily eliminated by the newprocess described in the present invention. The process of the presentinvention is a simple one with quantitative conversions and does notgenerate effluents and hence environment friendly. This is achievedthrough designing this novel process that avoids solvents includinghalogenated ones, reagents like p-toluene sulphonyl chloride and organicbases.

The successful application of this methodology has been demonstrated byconverting water-soluble bis halides of cinnamidoalkylamine to waterinsoluble tosylates. This is again significant in view of the fact thatwater insoluble quaternary UV-absorbers are more substantive thanwater-soluble ones [Soap, Perfumery & Cosmetics, 28–30, August, 2002].

EXAMPLES

The invention will now be illustrated with the help of examples. Theexamples are by way of illustrations only and in no way restrict thescope of invention.

Alkyl halides were obtained from Henkel. p-Toluene sulphonic acid wasobtained from Aldrich. p-Methoxy cinnamidopropyldimethylamine andp-N,N-dimethylamino benzamidopropyl dimethylamine were synthesised asper literature procedures [U.S. Pat. No. 5,427,773 (1995), U.S. Pat. No.6,613,340 (2003)]. 1,1′-oxy bis[(4-methoxy cinnamidopropyl dimethylammonio) ethane] dichloride was prepared according to U.S. Pat. No.6,426,435 (2002).

Example I Process for Preparation p-methoxycinnamidopropyldimethyllauryl ammonium tosylate

(The compound of Formula I, wherein, ArCO=p-methoxy cinnamoyl; R₁=H; R₂,R₃=CH₃; n=3; R₄=—C₁₂H₂₅).

a) Preparation of p-methoxy cinnamidopropyldimethyllauryl ammoniumchloride

A mixture of lauryl chloride (7.8 g, 38.17 mmol) and p-methoxycinnamidopropyldimethyl amine (10.0 g, 38.17 mmol) was stirred underblanket of nitrogen at 110° C. for 20 hours. The progress of reactionwas monitored by estimation of unquaternised amine. Estimated chlorideion and free amidoamine was found to be 7.6% and 0.12% respectively. Oncooling, the reaction yielded the quaternary ammonium compound (17.78 g,99.9%) as pale yellow solid.

b) Preparation of p-methoxy cinnamidopropyldimethyllauryl ammoniumtosylate

p-Methoxy cinnamidopropyldimethyllauryl ammonium chloride (17.78 g,38.11 mmol) was dissolved in water (60 ml) to make 30% solution. To thisstirred solution, sodium p-toluene sulphonate (7.4 g, 38.14 mmol) wasadded and the separated pale yellow coloured solid was subsequentlywashed with water, filtered and dried to yield the correspondingtosylate (22.9 g, 99.83%) as off-white solid, m.p. 128–130° C. Chlorideion was totally absent in the product.

IR (CH₂Cl₂): 3465, 3286, 3052, 2920, 1659, 1617 cm⁻¹.

¹H NMR (CDCl₃, 300 MHz): δ 0.87 (3H, t, J=6.3 Hz), 1.18 (18H, broadsignal), 1.58 (2H, unresolved multiplet), 2.10 (2H, unresolvedmultiplet), 2.32 (3H, singlet, methyl of tosyl), 3.13 (6H, singlet, twomethyl on nitrogen), 3.20 (2H, unresolved multiplet), 3.45 (2H,unresolved multiplet), 3.68 (2H, unresolved multiplet), 3.78 (3H,singlet, OCH₃), 6.52 (1H, d, J=15.6 Hz), 6.76 (2H, d, J=8.4 Hz), 7.14(2H, d, J=6.0 Hz), 7.31 (2H, d, J=8.6 Hz), 7.48 (1H, d, J=15.6 Hz), 7.78(2H, d, J=7.8 Hz).

¹³C NMR (125 MHz, CDCl₃): δ 14.10, 21.27, 22.69, 26.35, 29.23, 29.34,29.51, 29.64, 31.93, 36.38, 50.67, 55.24, 62.47, 64.24, 114.10, 119.43,125.83, 127.92, 128.89, 129.47, 139.56, 143.87, 160.67, & 167.25.

The molar extinction coefficient, ε was found to be 25,000 at λmax 310nm in methanol. The final compound was analysed on HPLC usingion-pairing technique. The mobile phase employed for ion-pairingcomprised of 0.1 M octane sulphonic acid in aqueous methanol (80:30).Reversed phase column Chromspher C8 was used with mobile phase flow rateof 1.0 ml/min. The detection was done at 280 nm. The purity of finalcompound from this analysis was found to be 99.9%.

The spectral and chromatographic data were in total agreement with thereported values.

Example II Process for Preparation of p-N,N-dimethylaminobenzamidopropyldimethyl lauryl ammonium tosylate

(The compound of Formula I, wherein, ArCO=p-N,N-dimethylamino benzoyl;R₁=H; R₂, R₃=CH₃; n=3; R₄=—C₁₂H₂₅).

a) Preparation of p-N,N-dimethylamino benzamidopropyl dimethyl laurylammonium chloride

A mixture of lauryl chloride (2.46 g, 12.05 mmol) andp-N,N-dimethylamino benzamido propyldimethyl amine (3.0 g, 12.05 mmol)was stirred under blanket of nitrogen at 110° C. for 20 hours. Theprogress of reaction was monitored by estimation of unquaternised amineas well as chloride ion. Estimated chloride ion and free amidoamine wasfound to be 7.83% and 0.15% respectively. On cooling, the reactionyielded the quaternary ammonium compound (5.455 g, 99.9%) as pale yellowsolid.

b) Preparation of p-N,N-dimethylamino benzamidopropyl dimethyl laurylammonium chloride tosylate

p-N,N-Dimethylamino benzamidopropyldimethyllauryl ammonium chloride(5.455 g, 12.03 mmol) was dissolved in water to make 30% solution. Tothis stirred solution, sodium p-toluene sulphonate (2.34 g, 12.06 mmol)was added and the separated pale yellow coloured solid was subsequentlywashed with water, filtered and dried to yield the correspondingtosylate (7.08 g, 99.93%) as pale yellow coloured solid. Chloride ionwas totally absent in the product.

The spectral data (UV, IR and ¹H NMR) was found to be identical with theone obtained by literature route. Reversed phase HPLC showed it to be99.9% pure.

Example III Process for Preparation of 1,1′-oxy bis[(4-methoxycinnamidopropyl dimethyl ammonio) ethane]ditosylate

(The compound of Formula VI, wherein, ArCO=p-methoxy cinnamoyl; R₁=H;R₂, R₃=CH₃; n=3; m=1).

Isopropanolic solution of 1,1′-oxy bis[(4-methoxy cinnamidopropyldimethyl ammonio) ethane] dichloride (20.0 g, 19.5 mmol) was stirredwith sodium p-toluene sulphonic acid (7.66 g, 39.5 mmol) at 80° C. for 8hours. The sodium chloride separated was filtered to give isopropanolicsolution of bis tosylate. IPA removal gave bis quaternary tosylate assticky solid that was found to be water insoluble. It has very goodsolubility in alcohols and glycols.

¹H NMR of dried bis tosylate confirmed the structure. The filteredsodium chloride was found to be quantitative.

1. A process for preparing quaternary ammonium tosylates of Formula VI,

where: each ArCO is independently p-N,N-dimethylamino benzoyl orp-methoxy cinnamoyl; R₁ is selected from H or alkyl groups containingfrom 1 to 6 carbon atoms; R₂ and R₃ are independently selected fromalkyl groups containing from 1 to 12 carbon atoms; n is an integerhaving values from 1 to 6; and m is an integer having values from 1 to10; the process comprising: reacting a compound of Formula V with sodiump-toluene sulphonate, the respective substituents ArCO, R₁, R₂, R₃, nand m of Formula V, being as defined for the compounds of Formula VI inthis claim:


2. A water insoluble quaternary ammonium bis tosylate of Formula VI;

where: each ArCO is independently p-N,N-dimethylamino benzoyl orp-methoxy cinnamoyl; R₁ is selected from H or alkyl groups containingfrom 1 to 6 carbon atoms, R₂ and R₃ are independently selected fromalkyl groups containing from 1 to 12 carbon atoms; n is an integerhaving values from 1 to 6; and m is an integer having values from 1 to10.